The overall goal of this research is to determine the physiological role of the AE2 anion exchanger in epithelial cells that line the colon and biliary system. AE2 functions to exchange one chloride for one bicarbonate ion across the membrane of many cell types. This activity results in net chloride movement into the cell (where it is available for secretion by other transporters) and net bicarbonate movement out of the cell. In the colon, AE2 has been proposed to mediate chloride uptake into the epithelial cells to support transepithelial secretion and to provide an exit pathway for bicarbonate from the cell during bicarbonate absorption. In the biliary system, AE2 is believed to be expressed on the apical membrane and mediate the electrically-silent component of bicarbonate secretion into bile. Using gene-targeting technology, the aims of this proposal are i) to test the hypotheses that AE2 is critical to chloride and bicarbonate transport in colonic and biliary epithelial cells and 2) develop an intestine-specific AE2 knockout to evaluate the role of AE2 in colonic bicarbonate absorption.